1. Field of the Invention
This invention relates to implants having variable permeability for use in biological applications such as osteochondral autografts, tissue scaffolds, bone regeneration fillers or the like and methods for making the implants.
More particularly, this invention relates to compositions having variable or differential permeability where the compositions can have areas, regions and/or surfaces that are essentially or substantially impermeable, while other areas, regions or surfaces can be highly permeable, methods for making the compositions and to methods for using the compositions.
2. Background Information and Description of the Related Art
Successful design of an implant to replace skeletal tissue requires knowledge of the structure and mechanical properties of bone and an understanding of the means by which grafts become incorporated into the body. This information can then be used to define desirable characteristics of implants to ensure that the implants function in a manner comparable to organic tissue.
The mechanical properties of bone are related to the internal organization of the material. The porosity of cortical bone tissue (typically 10%) is primarily a function of the density of voids in the bone. In contrast, cancellous/trabecular bone is a network of small, interconnected plates and rods of individual trabeculae with relatively large spaces between the trabeculae. Trabecular bone has a porosity of 50-90% which is a function of the space between the trabeculae. The material properties of bone are based on determinations of the elastic modulus, compressive and tensile strengths.
As a general rule, bone is stronger in compression than in tension and cortical bone is stronger than trabecular bone. Ranges of reported elastic modulus have been from 10 MPa to 25 GPa (10 MPa to 2 GPa for cancellous bone; 4 to 25 GPa for cortical and cancellous bone); compressive strength between 40 and 280 MPa (40 to 280 MPa for cancellous bone; 138 to 193 MPa for cortical bone); and tensile strength between 3.5 MPa and 150 MPa (3.5 to 150 MPa for cancellous bone; 69 to 133 MPa for cortical bone).
Mechanisms by which bone may fail include brittle fracture from impact loading and fatigue from constant or cyclic stress. Stresses may act in tension, compression, and/or shear along one or more of the axes of the bone. A synthetic bone substitute should resist failure by any of these stresses at their physiological levels. A factor of safety on the strength of the implant may ensure that the implant will be structurally sound when subject to hyperphysiological stresses.
A graft may be necessary when bone fails and does not repair itself in the normal amount of time or when bone loss occurs through fracture or tumor. Bone grafts must serve a dual function: to provide mechanical stability and to be a source of osteogenesis. Since skeletal injuries are repaired by the regeneration of bone rather than by the formation of scar tissue, grafting is a viable means of promoting healing of osseous defects. Osteoinduction and osteoconduction are two mechanisms by which a graft may stimulate the growth of new bone. In the former case, inductive signals of little-understood nature lead to the phenotypic conversion of connective tissue cells to bone cells. In the latter, the implant provides a scaffold for bony ingrowth.
The bone remodeling cycle is a continuous event involving the resorption of pre-existing bone by osteoclasts and the formation of new bone by the work of osteoblasts. Normally, these two phases are synchronous and bone mass remains constant. However, the processes become uncoupled when bone defects heal and grafts are incorporated. Osteoclasts resorb the graft, a process which may take months. More porous grafts revascularize more quickly and graft resorption is more complete. After graft has been resorbed, bone formation begins. Bone mass and mechanical strength return to near normal.
Present methods for the repair of bony defects include grafts of organic and synthetic construction. Three types of organic grafts are commonly used: autografts, allografts, and xenografts. An autograft is tissue transplanted from one site to another in the patient. The benefits of using the patient's tissue are that the graft will not evoke a strong immune response and that the material is vascularized, which allows for speedy incorporation. However, using an autograft requires a second surgery, which increases the risk of infection and introduces additional weakness at the harvest site.
Further, bone available for grafting may be removed from a limited number of sites, for example, the fibula, ribs and iliac crest. An allograft is tissue taken from a different organism of the same species, and a xenograft from an organism of a different species. The latter types of tissue are readily available in larger quantities than autografts, but genetic differences between the donor and recipient may lead to rejection of the graft.
Synthetic implants may obviate many of the problems associated with organic grafts. Further, synthetics can be produced in a variety of stock shapes and sizes, enabling the surgeon to select implants as his needs dictate. Metals, calcium phosphate ceramics and polymers have all been used in grafting applications.
Biodegradable polymers are used in medicine as suture and pins for fracture fixation. These materials are well suited to implantation as they can serve as a temporary scaffold to be replaced by host tissue, degrade by hydrolysis to non-toxic products, and be excreted, as described by Kulkarni, et al., J. Biomedical Materials Research, 5, 169-81 (1971); Hollinger, J. O. and G. C. Battistone, "Biodegradable Bone Repair Materials," Clinical Orthopedics and Related Research, 207, 290-305 (1986), incorporated herein by reference.
Four polymers widely used in medical applications are poly(paradioxanone) (PDS), poly(dl-lactic acid) (PLA), poly(dl-glycolic acid) (PGA), and copolymers of dl-lactic acid and dl-glycolic acid (PLG). Copolymerization enables modulation of the degradation time of the material. By changing the ratios of crystalline to amorphous polymers during polymerization, properties of the resulting material can be altered to suit the needs of the application. For example, PLA is crystalline and a higher PLA content in a PLG copolymer results in a longer degradation time, a characteristic which may be desirable if a bone defect requires structural support for an extended period of time. Conversely, a short degradation time may be desirable if ingrowth of new tissue occurs quickly and new cells need space to proliferate within the implant.
Several patents have dealt with synthetic implants for use in reconstruction, repair and/or regeneration of tissues and/or organs and especially skeletal tissue including the following United States Patents.
U.S. Pat. No. 5,631,015 discloses a sustained release parenteral composition comprising an admixture of at least one drug to be delivered in a therapeutically effective amount and a bioabsorbable polymer containing one or more lactone monomers that is a liquid at body temperature, provided in an amount effective to sustain or extend the release rate of the drug and is incorporated herein by reference.
U.S. Pat. No. 5,626,861 discloses a method for making biodegradable composition involving mixing hydroxyapatite particles with a non-aqueous solution of a biodegradable, biocompatible polymer solvent; suspending particles of an inert waterleachable material in the solution, provided that the material is not soluble in the solution; removing the solvent; and removing the inert leachable material to yield a composite having pores and is incorporated herein by reference.
U.S. Pat. No. 5,516,532 discloses a demineralized ground bone or cartilage matrix where the phosphate content can be further reduced by treatment of the matrix with acid phosphatase, which removes residual organic phosphate and is incorporated herein by reference. The material is useful in a method of treatment of vesicouretal reflux and other disorders where a bulking agent is effective in correcting the defect.
U.S. Pat. No. 5,492,697 discloses a biodegradable implant for placement in nonunion bone fractures. The implant is a flat plate or disk having a thickness of between about 1 mm and about 15% of the length of the bone, interconnected micropores, and canals substantially equivalent in size and spacing to the naturally occurring Haversian canals and is incorporated herein by reference. The implant is formed form biodegradable polymers such as polylactic acid-polyglycolic acid copolymer by a gel casting technique followed by solvent extraction to precipitate the implant as a microporous solid.
U.S. Pat. No. 5,366,756 discloses a porous bioabsorable surgical implant material is prepared by coating particles of bioasborbable polymer with a tissue ingrowth promoter and is incorporated herein by reference.
U.S. Pat. No. 5,344,654 discloses a prosthetic device comprising a prosthesis coated with substantially pure osteogenic protein, which can be contained in a biocompatible polymer and is incorporated herein by reference.
U.S. Pat. No. 5,324,519 discloses a composition comprising a liquid formulation of a biodegradable, bioerodible, biocompatible thermoplastic polymer that is insoluble in aqueous or body fluid, and a biocompatible organic solvent that is miscible or dispersible in aqueous or body fluid and dissolves the thermoplastic polymer and is incorporated herein by reference.
U.S. Pat. No. 5,286,763 discloses bioerodible polymers which degrade completely into nontoxic residues over a clinically useful period of time, including polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid and copolymers thereof, are used for the delivery of bioactive agents directly into bone and is incorporated herein by reference.
U.S. Pat. Nos. 5,162,114, 5,171,574 and 4,975,526 discloses a matrix material comprising biocompatible mineral-free type I collagen, xenogenic to the host and biodegradable there within and is incorporated herein by reference.
Although these patents relate generally to various tissue scaffolds, biocompatible fillers or bone grafting compositions, there is still a need in the art for new filler compositions that provide increased functionality especially for the temporary or transient control of bleeding into tissue damaged areas while tissue reconstruction, regeneration and repair take place.